Innate lymphoid cells (ILCs) generally fall into four categories, TCRγδ T cells, dendritic cells (DCs), macrophages, natural killer (NK) cells, and subpopulations of each ( 26.3 ). ILCs are distinctively different from adaptive immune cells by their lack of “antigen” specificity for the offending agents and their ability to distinguish self from non-self through recognition of PAMPs present on the pathogens. Since most inhaled substances are nonpathogenic, the body has developed a specialized recognition system to identify harmful pathogenic substances and organisms. Rather than specific antigen recognition, this system enables discrimination of self from non-self material through the recognition of PAMPs on the pathogenic organisms/substances, which are then recognized by a family of receptors on host defense cells (i.e., ILCs) called pattern recognition receptors (PRRs). PAMPs are common distinguishing features on many pathogens and are composed of peptidoglycans, lipopolysaccharides, and unmethylated 5′-C-phosphate-G-3′ (CpG) DNA, which bind to their corresponding PPRs on ILCs. There are two major classifications for PRRs: toll-like receptors (TLRs), which are expressed mainly on cell surfaces, and nucleotide-oligomerization domain (NOD) receptors, which are expressed intracellularly in the cytoplasma of ILCs. Both of these pathways activate nuclear factor Kβ (NFKβ), a transcription factor, which stimulates release of proinflammatory cytokines, as well the antiviral type I interferons (IFN-α and IFN-β). The TLRs are a family of transmembrane proteins with different specificities for various pathogens. TLR-2 is specific for lipoteichoic acids associated with gram-positive bacteria, whereas TLR-4 is specific for lipopolysaccharide (endotoxin), a product of gram-negative bacteria. In the lung, bronchial epithelial cells, macrophages, DCs, mast cells, eosinophils, and alveolar type II epithelial cells express both TLR-2 and TLR-4. Other TLRs are specific for viruses: TLR-3 binds to double-stranded RNA viruses, and TLR-7 and TLR-8 bind to single-stranded RNA viruses. NK cells express TLR-3, TLR-7, and TLR-8 and plasmacytoid DCs, eosinophils, and B cells express TLR-7. A variety of phagocytic cells and DCs in the lung and other mucosal tissues also express TLRs. Thus in addition to classical phagocytic cells, bronchial and alveolar epithelial cells play active roles in host defense by means of the PAMP-PRR nexus.
Perhaps the most unique and intriguing aspect of this specialized mucosal defense system is the ability of ILCs to respond to pathogens immediately, as opposed to the days or weeks it takes to mount a classical TCRαβ T cell adaptive immune response with clonal expansion and memory. The fast response, and the lack thereof for innocuous substances, are highly advantageous in the mucosal tissues, which are common sites for parasitic invasion and toxic chemical exposure. In addition, many of the ILCs demonstrate plasticity, meaning that they can be induced by the environment (i.e., cytokines) to alter their functionality to either a proinflammatory or regulatory (suppressive) phentoype.